Anticancer agents are administered in treatments of cancer patients at present. However, their life-prolongation rates are undesirably low, and moreover, cancer patients administered with an anticancer agent are forced to tolerate severe side effects such as fever, nausea, epilation, chill, fatigue, immune malfunction, gastrointestinal disorder, liver disorder, and kidney disorder, which becomes a cause of significant deterioration of the QOL (Quality of Life) of the cancer patients. Furthermore, reduction of sensitivity of cancer cells to anticancer agents, caused by the use of the anticancer agents, may lead to prolonged administration period of administration of the anticancer agents and increase of doses, and as a result, deaths resulting from side effects of the anticancer agents are often observed. Therefore, the administration of anticancer agents may spoil advantages of patients, as well as significantly diminish social and economic benefits. This is caused by the fact that anticancer agents, which are expectedly used to exhibit selective cytotoxicity to cancer cells that disorderly divide and proliferate, actually act cytotoxically on normal cells, particularly on cells in the intestine and marrow.
In recent years, reports have been made on caffeine which is a low molecule organic compound and UCN-01(7-hydroxy staurosporine) having actions to enhance radiation susceptibility of cancer cells which are radiation resistant (J. Biol. Chem., 275, 5600-5605, 2000; J. Biol. Chem., 276, 17693-17698, 2001). Cancer therapy by radiation is also based on the mode of action of artificial injury of DNAs, and is considered to be basically equivalent to anticancer agents such as bleomycin based on the mode of action of DNA injury. Accordingly, it is believed that a drug that enhances selective toxicity to cancer cells can be developed even for anticancer agents based on the mode of action of DNA injury which are available at present.
In fact, it is reported that caffeine increases the actions of anticancer agents such as adriamycin, cisplatin, cyclophosphamide, and mitomycin C based on the mode of action of DNA injury (Jpn. J. Cancer. Res., 80, 83-88, 1989). However, potency remains insufficient, and separation from toxicity is unsatisfactory. UCN-01 is also reported to enhance actions of several kinds of anticancer agents based on the mode of action of DNA injury (Invest. New Drugs, 18, 95-107, 2000).
As for the mode of action of the potentiation of anticancer agents, the action is presumed to be based on a destruction of a certain part of the cell cycle (for example, G1 period and G2 period: Cancer Res., 60, 2108-2112, 2000; Cancer Res., 59, 4375-4382(1999), since caffeine and UCN-01 inhibit protein kinases involved in a control of a cell cycle (J. Biol. Chem., 275, 10342-10348, 2000; Cancer Res., 61, 1065-1072, 2001). However, no conclusive evidence has been obtained. In addition, since caffeine and UNC-01 as a staurosporin derivative have inhibitory actions against multiple kinds of protein kinases (Biochem. Biophys. Res. Commun., 219, 778-783, 1996; Acta Pharmacol. Sin., 21, 35-40, 2000), a possibility of involvement of a mechanism other than the destruction of the cell cycle can not be denied. Accordingly, a clear mode of action remains unidentified. Furthermore, there is a high possibility that these agents have inhibitory actions also against protein kinases participating in intracellular signal transduction, which is considered to be a possible cause of inducing serious side effects.
As explained above, no effective means is available at present to solve various problems caused by the cancer therapies based on the mode of action of DNA injury. Developments of new drugs or therapies, that potentiate the effects of available anticancer agents and radiation therapy based on the mode of action of DNA injury and that enhance selectivity to cancer cells to decrease side effects, will contribute to increase the QOL and advantages of cancer patients as well as social and economic benefits.